China is a country with high incidences of hepatoma. There are approximately 350,000 cases of newly discovered hepatoma each year, accounting for about 50% of the world's new hepatoma cases. There are 300,000 cases of death caused by hepatoma each year, and the mortality rate thereof is the second highest in cancer patients in China. A main reason for this high mortality is that most patients with hepatoma are already in advanced stage of disease upon diagnosis. The existing treatment methods, include surgery, intervention and radiation therapies, are unable to effectively improve the survival rate of patients with advanced hepatoma (the 5-year survival rate is approximately 20%). Current chemotherapy drugs for cancer such as fluorouracil, doxorubicin and cisplatin are not effective in hepatoma treatment and have toxic side effects. Nexavar (sorafenib), developed and produced by the German company Bayer in 2008, is the only approved drug for advanced hepatoma so far. However, it only temporarily delays the progression of hepatoma.
Clinically, more than 70% of the patients in China with advanced hepatoma are HBV (hepatitis B virus) positive. In recent years, studies have shown that HBV gene fragments integrate into the genome of hepatoma patients at different sites with different levels, resulting in changes in the regulation of multiple molecular pathways in cells, as the carcinogenesis process. Based on these findings, targeting abnormal molecular pathways in HBV integrated hepatoma cells is a new direction of chemotherapy drugs to selectively kill hepatoma cells for hepatoma. For example, the level of cytosolic thymidine kinase (TK1) is closely related to the expression of cell division cycle. In normal cells, it is expressed only in the S phase and rapidly degraded upon entering the G2 phase. Thus, the expression level of thymidine kinase in normal liver cells is too low to detect. However, it has been found persistently in cancer patients that thymidine kinase is highly expressed, which is consistent with the rapid growth of cancer cells. Therefore, thymidine kinase is considered to be one of the important targets for cancer treatment in recent years. Agents such as Zidovudine (AZT) and Acyclovir can be converted into the corresponding 5′-phosphate by the high expression of thymidine kinase, resulting in the inhibition of viral polymerase to prevent viral nucleic acid synthesis. However, acyclovir and zidovudine are not effective in cancer treatment, mainly because they only selectively inhibit the viral polymerase. Currently, Zidovudine derivatives have been reported as potent inhibitors of thymidine kinase, yet no significant biological effect thereof is found in cancer cells. Therefore, it is critical to design novel chemical molecules for selectively killing HBV-integrated cancer cells with high expression of thymidine kinase.